The in vitro fertilization of zona-free hamster eggs was originally proposed by us as a test for human sperm fertilizing ability. We have subsequently presented data to establish the use of such a sperm penetration assay to differentiate between fertile and potentially infertile or subfertile semen samples. Numerous investigators have verified the ability of such an in vitro fertilization procedure to evaluate semen quality. This test appears to be capable of assessing the ability of human spermatozoa to undergo capacitation, acrosome reaction, and ovum fusion. The purpose of this proposal is to study the effectiveness of various treatments currently available for the infertile male. The assessment of treatment modalities for infertile males will involve using the zona-free egg penetration assay as an indicator of fertility status before and after treatment. Men with varicocele and infertility are to be tested before and after surgical ligation of the internal spermatic vein. The effectiveness of clomiphene citrate therapy in men will be evaluated by doing a double blind crossover study with subfertile patients. Removal or reduction of white blood cells in subfertile samples will be accomplished by both antibiotic treatment and physical removal of the cells. The effectiveness of white blood cell removal as a treatment will be evaluated by monitoring changes in routine semen parameters and penetration rates in the zona-free egg test system. The fourth treatment modality will involve washing spermatozoa in media which potentially enhances their fertilizing ability and doing intrauterine insemination in the wife as well as insemination of zona-free hamster eggs. An evaluation of treatment efficacy in subfertile males should help to clarify the validity of such treatments. Using the zona-free egg assay we will eliminate the confounding variable of the female partner and thus make our results less equivocal.